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Colloidal Aggregators in Biochemical SARS-CoV-2 Repurposing Screens.
Henry R O'Donnell1, Tia A Tummino1,2,3, Conner Bardine4
1Department of Pharmaceutical Chemistry, University of California San Francisco (UCSF), San Francisco, California 94158-2550, United States.
Journal of Medicinal Chemistry
|November 23, 2021
Summary
Many drugs repurposed for COVID-19 may be artifacts due to colloidal aggregation. This study highlights the need to detect such artifacts to find genuinely effective treatments for coronavirus disease 2019.
Area of Science:
- Biochemistry
- Drug Discovery
- Materials Science
Background:
- Drug repurposing is crucial for combating COVID-19.
- In vitro screening assays can yield false positives due to artifacts like colloidal aggregation.
- Colloidal aggregation can mimic genuine drug activity in biochemical assays.
Purpose of the Study:
- To investigate the prevalence and impact of colloidal aggregation as a screening artifact in COVID-19 drug repurposing.
- To identify drugs that exhibit aggregation at concentrations relevant to biochemical assays.
- To emphasize the importance of detecting aggregation artifacts for reliable drug discovery.
Main Methods:
- Dynamic light scattering (DLS) was used to detect colloidal aggregation.
- Detergent-based enzyme counter screening was employed to identify aggregation-related artifacts.
- Fifty-six drugs with reported activity were tested, along with 15 selected based on physical properties of known aggregators.
Main Results:
- Nineteen of 56 tested drugs formed colloids at concentrations near their reported IC50 values.
- An additional 14 drugs showed problematic aggregation behavior.
- Six of 15 selected drugs aggregated at micromolar concentrations.
Conclusions:
- A significant number of drugs repurposed for SARS-CoV-2 in biochemical assays may be artifacts of colloidal aggregation.
- Colloidal aggregation can be a general artifact in drug screening at relevant concentrations.
- Developing rapid methods to detect aggregation artifacts is essential for focusing research on truly effective COVID-19 therapeutics.
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